PROJECT SUMMARY/ABSTRACT Sensory abnormalities characterize a wide range of neurodevelopmental disorders. In autism spectrum disorder (ASD), for example, sensory overload is one of the most frequently reported symptoms. Abnormal regulation of sensory information flow (sensory gating) is also observed in schizophrenia and ADHD, and is thought to contribute to overall cognitive dysfunction across all these conditions. Despite its central importance, little is known about the neurobiology of sensory gating, and even less is known about its failure in disease. This proposal aims to address this critical gap. The neocortex is requires for higher level sensory processing, but early processing and transmission of sensory information is performed by the thalamus. We and others have found that thalamic sensory input is controlled by the thalamic reticular nucleus (TRN), a shell of GABAergic neurons surrounding thalamic relay nuclei. The TRN is composed of individual subnetworks, each controlling thalamic flow in a modality-specific manner. Recent clinical data have shown thalamic and TRN dysfunction in neurodevelopmental disorders. Given the critical role for TRN in sensory processing, we expect perturbations in its circuits to pathologically augment cortical sensory input, explaining several clinical symptoms. In sleep, TRN dysfunction may result in increased sensory-related arousals, while in attention irrelevant inputs may become much more distracting. As such, a `leaky thalamus' may have profound consequences on behavior and cognition across disorders. In this proposal, we will test the leaky thalamus framework by manipulating thalamic inhibition in mice while monitoring the impact on sensory function and related behaviors. In addition, we will investigate the therapeutic potential of reversing thalamic inhibition deficits in models of human neurodevelopmental disorders.